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Quantitative mapping of the in vivo O-GalNAc glycoproteome in mouse tissues identifies GalNAc-T2 O-glycosites in metabolic disorder.

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Title: Quantitative mapping of the in vivo O-GalNAc glycoproteome in mouse tissues identifies GalNAc-T2 O-glycosites in metabolic disorder.
Authors: Weiming Yang1, Tian, E.2, Chernish, Aliona1, McCluggage, Peggy1, Dalal, Kruti1, Lara, Alexander1, Ten Hagen, Kelly G.2, Tabak, Lawrence A.1 lawrence.tabak@nih.gov
Source: Proceedings of the National Academy of Sciences of the United States of America. 10/24/2023, Vol. 120 Issue 43, p1-11. 22p.
Subjects: Metabolic disorders, Querying (Computer science), Workflow software, Congenital disorders, Mice
Abstract: The family of GalNAc-Ts (GalNAcpolypeptide:N-Acetylgalactosaminyl transferases) catalyzes the first committed step in the synthesis of O-glycans, which is an abundant and biologically important protein modification. Abnormalities in the activity of individual GalNAc-Ts can result in congenital disorders of O-glycosylation (CDG) and influence a broad array of biological functions. How site-specific O-glycans regulate biology is unclear. Compiling in vivo O-glycosites would be an invaluable step in determining the function of site-specific O-glycans. We integrated chemical and enzymatic conditions that cleave O-glycosites, a higher-energy dissociation product ions-triggered electron-transfer/higher-energy collision dissociation mass spectrometry (MS) workflow and software to study nine mouse tissues and whole blood. We identified 2,154 O-glycosites from 595 glycoproteins. The O-glycosites and glycoproteins displayed consensus motifs and shared functions as classified by Gene Ontology terms. Limited overlap of O-glycosites was observed with protein O-GlcNAcylation and phosphorylation sites. Quantitative glycoproteomics and proteomics revealed a tissue-specific regulation of O-glycosites that the differential expression of Galnt isoenzymes in tissues partly contributes to. We examined the Galnt2-null mouse model, which phenocopies congenital disorder of glycosylation involving GALNT2 and revealed a network of glycoproteins that lack GalNAc-T2-specific O-glycans. The known direct and indirect functions of these glycoproteins appear consistent with the complex metabolic phenotypes observed in the Galnt2-null animals. Through this study and interrogation of databases and the literature, we have compiled an atlas of experimentally identified mouse O-glycosites consisting of 2,925 O-glycosites from 758 glycoproteins. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Quantitative mapping of the in vivo O-GalNAc glycoproteome in mouse tissues identifies GalNAc-T2 O-glycosites in metabolic disorder.
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  Data: <searchLink fieldCode="AR" term="%22Weiming+Yang%22">Weiming Yang</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Tian%2C+E%2E%22">Tian, E.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Chernish%2C+Aliona%22">Chernish, Aliona</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22McCluggage%2C+Peggy%22">McCluggage, Peggy</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Dalal%2C+Kruti%22">Dalal, Kruti</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Lara%2C+Alexander%22">Lara, Alexander</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Ten+Hagen%2C+Kelly+G%2E%22">Ten Hagen, Kelly G.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Tabak%2C+Lawrence+A%2E%22">Tabak, Lawrence A.</searchLink><relatesTo>1</relatesTo><i> lawrence.tabak@nih.gov</i>
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  Data: <searchLink fieldCode="DE" term="%22Metabolic+disorders%22">Metabolic disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Querying+%28Computer+science%29%22">Querying (Computer science)</searchLink><br /><searchLink fieldCode="DE" term="%22Workflow+software%22">Workflow software</searchLink><br /><searchLink fieldCode="DE" term="%22Congenital+disorders%22">Congenital disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Mice%22">Mice</searchLink>
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  Data: The family of GalNAc-Ts (GalNAcpolypeptide:N-Acetylgalactosaminyl transferases) catalyzes the first committed step in the synthesis of O-glycans, which is an abundant and biologically important protein modification. Abnormalities in the activity of individual GalNAc-Ts can result in congenital disorders of O-glycosylation (CDG) and influence a broad array of biological functions. How site-specific O-glycans regulate biology is unclear. Compiling in vivo O-glycosites would be an invaluable step in determining the function of site-specific O-glycans. We integrated chemical and enzymatic conditions that cleave O-glycosites, a higher-energy dissociation product ions-triggered electron-transfer/higher-energy collision dissociation mass spectrometry (MS) workflow and software to study nine mouse tissues and whole blood. We identified 2,154 O-glycosites from 595 glycoproteins. The O-glycosites and glycoproteins displayed consensus motifs and shared functions as classified by Gene Ontology terms. Limited overlap of O-glycosites was observed with protein O-GlcNAcylation and phosphorylation sites. Quantitative glycoproteomics and proteomics revealed a tissue-specific regulation of O-glycosites that the differential expression of Galnt isoenzymes in tissues partly contributes to. We examined the Galnt2-null mouse model, which phenocopies congenital disorder of glycosylation involving GALNT2 and revealed a network of glycoproteins that lack GalNAc-T2-specific O-glycans. The known direct and indirect functions of these glycoproteins appear consistent with the complex metabolic phenotypes observed in the Galnt2-null animals. Through this study and interrogation of databases and the literature, we have compiled an atlas of experimentally identified mouse O-glycosites consisting of 2,925 O-glycosites from 758 glycoproteins. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2303703120
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        Text: English
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      – SubjectFull: Metabolic disorders
        Type: general
      – SubjectFull: Querying (Computer science)
        Type: general
      – SubjectFull: Workflow software
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      – SubjectFull: Congenital disorders
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      – SubjectFull: Mice
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      – TitleFull: Quantitative mapping of the in vivo O-GalNAc glycoproteome in mouse tissues identifies GalNAc-T2 O-glycosites in metabolic disorder.
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              Text: 10/24/2023
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              Y: 2023
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